PB1865: NPM1-MUT MONITORING DURING GILTERITINIB TREATMENT IDENTIFIES DIFFERENT DYNAMICAL PATTERNS IN RESPONSIVE PATIENTS
Authors: Chiara Sartor, Emanuela Ottaviani, Jacopo Nanni, Raffaele Ciruolo, Gianluca Cristiano, Letizia Zannoni, Federico Zingarelli, Lorenza Bandini, Agnese Patuelli, Claudia Venturi, Valentina Robustellu, Dorian Forte, Michele Cavo, Antonio Curti, Cristina Papayannidis
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: Gilteritinib (Gilt) is a potent FLT3-inhibitor (FLT3i) approved for the treatment of relapsed/refractory (R/R) FLT3-positive (FLT3+) acute myeloid leukemia (AML). Approximately 45% of FLT3+ AML harbor concomitant NPM1 mutations (NPM1mut). Diversely from FLT3 mutations, NPM1mut are reliable leukemia specific markers for which minimal residual disease (MRD) monitoring with NPM1mut-specific qRT-PCR assay is standardized. NPM1mut-MRD has prognostic role in chemotherapy and venetoclax-based regimes and correlates with disease burden. The role of NPM1mut-MRD under treatment with a FLT3i potentially associated with differentiating effect is currently unknown. Aims: To explore the dynamics of NPM1mut transcript in disease monitoring in FLT3+NPM1mut AML patients (pts) treated with Gilt. Methods: R/R FLT3+ NPM1mut AML pts responsive to Gilt were retrospectively evaluated. Key inclusion criteria were 1) achievement of at least morphological leukemia free state (MLFS); 2) availability of at least 2 on-treatment time-points for NPM1mut evaluation, excluding relapse and post hematopoietic stem cell transplantation (HSCT). Disease was assessed on bone marrow (BM) with NPM1mut-specific qRT-PCR; results are reported as NPM1mut copy number/ABL copy number x 100. Significant increase/decrease between samples was defined as a variation >1 logarithm (log). Results: Twelve pts (median age at diagnosis, 57 ys; range 32-71 ys) treated with Gilt from 2018 to 2022 were analyzed. Eight of 12 (67%) were treated at first salvage (S1), 3 (25%) at S2, 1 (8%) at S3. Eight of 12 (67%) pts had previously received a FLT3i, 3 (25%) were FLT3i naïve; 1 pt unknown (enrollment in PBO-controlled trial). At diagnosis, nine (75%) pts had FLT3-ITD mutation, 2 had FLT3-TKD and 1 had both; AR was available for 8 pts, 3 had ARhigh and 5 had ARlow. At Gilt treatment, 10 (83%) pts had FLT3-ITD (7 ARhigh, 2 ARlow, 1 unknown), 2 FLT3-TKD. The most frequent comutation at diagnosis was DNMT3A, detectable in 8 of 9 (89%) pts with available next generation sequencing (NGS) myeloid panel. Median NPM1mut transcript at diagnosis was 165,95% (range, 51,36-3338,15), and at Gilt treatment 69,65% (range, 0,53-245). Median BM blast count was 20% (range, 5-90). Median n of Gilt cycles (maintenance cycles post-HSCT were excluded) was 5 (range 3-13). BM response (CR/CRh/CRi) was achieved after a median of 2 cycles (range, 1-5); 1 patient achieved MLFS. No patients developed differentiation syndrome. Concerning NPM1mut transcript we observed 3 possible patterns: 1) log reduction >1 (=3 pts); 2) log increase >1 (=4 pts); 3) stable values (=5 pts). Paired NPM1mut and FLT3-ITD AR evaluation was available for the 10 FLT3-ITD pts. In pts experiencing NPM1mut reduction, FLT3-ITD AR decreased in concordance with NPM1mut transcript (3 of 3 pts); in patients experiencing increase, FLT3-ITD was stable in 2 of 3 pts, 1 became FLT3neg; in patients with stable NPM1mut levels FLT3-ITD AR was stable (3 of 4), 1 became FLT3neg. Median follow-up is 13.4 mo (range, 5.6-52.0). Eight pts proceeded to HSCT, 2 died from NRM, and 6 are alive in CR. The 4 (33%) pts who did not undergo HSCT relapsed (3 belonged to the NPM1mut log increase group, 1 to the stable). NPM1mut transcript increase was observed in all 4 cases at relapse, confirming role as stable leukemia marker. At relapse, 1 pt was FLT3neg, 1 lost FLT3-TKD on treatment and acquired FLT3-ITD. Summary/Conclusion:NPM1mut transcript monitoring in Gilt sensitive pts may follow different dynamical patterns, possibly reflecting drug-induced differentiation and not necessarily correlating with disease burden. Keywords: FLT3, Acute myeloid leukemia, Minimal residual disease (MRD), flt3 inhibitor